The genetic disease cystic fibrosis (CF), which causes death primarily by predisposing the lungs to chronic infections, is presently a leading candidate for somatic gene therapy. However, the mouse model of CF does not develop lung disease, and no other animal model for CF exists. Other animal models could be of considerable usefulness for testing therapies. This proposal will evaluate a general approach for finding such models. Genetic screening, based on polymerase chain reaction single strand conformation polymorphism and heteroduplex analysis (PCR-SSCP/HA), will be used to test two hypotheses: (1) that DNA sequence variation (mutations + polymorphisms) within the CFTR gene is approximately equivalent in non- human primate and human populations, and (2) that across human populations, the aggregate frequency of disease causing mutations in CFTR (after subtraction of DeltaF508), provides a rough estimate of expected mutation frequencies in non-human primates. Confirmation of the second hypothesis will require the detection of one or more primates who are heterozygous for a disease-causing mutation in the CFTR gene. In humans, the combined carrier frequency rate in various populations for mutations other than DeltaF508 (about 500 mutations identified to date) is estimated to be about 1/85 to 1/150 equivalent to disease frequencies of about 1/30,000 to 1/90,000. The proposed research program is designed to have an about 95% chance of detecting a mutation at carrier frequencies corresponding to a disease rate of 1/1,000,000. When primates with candidate CF mutations on one chromosome are identified, we assess the effects of the mutation on CFTR trafficking and function. If the mutation disrupts CFTR function, a breeding program will be initiated to produce a renewable population of CF homozygous primates.